PTEN c.155A>T, p.(Asp52Val)

Reasoning

PM2 Supporting is met under the PTEN-specific VCEP. NM_000314.8:c.155A>T (p.Asp52Val) is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0. This satisfies the VCEP requirement for absence or allele frequency <0.00001 (0.001%) in gnomAD or another large sequenced population; no subpopulation allele count requiring the <0.00002 (0.002%) condition was reported.

Rule

PTEN VCEP PM2 Supporting: absent or allele frequency <0.00001 (0.001%) in gnomAD or another large sequenced population; if multiple alleles are present in a subpopulation, that subpopulation frequency must be <0.00002 (0.002%).

Evidence considered

• ClinGen PTEN Expert Panel Specification v3.2 permits PM2 Supporting when the variant is absent or present at <0.00001 (0.001%) allele frequency in gnomAD or another large sequenced population; if multiple alleles occur in a subpopulation, that subpopulation frequency must be <0.00002 (0.002%).
• The case bundle reports NM_000314.8:c.155A>T as absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0.

Sources

Reasoning

This is a missense variant in PTEN. The PTEN Expert Panel Version 3.2 framework designates PP2 as applicable at supporting strength for a missense variant in a gene with a low rate of benign missense variation where missense variation is a common disease mechanism. PTEN is therefore eligible for PP2 under the governing gene-specific framework.

Rule

Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease; PTEN VCEP strength: Supporting.

Evidence considered

• The normalized consequence is NP_000305.3:p.(Asp52Val), a missense change.
• The PTEN VCEP Version 3.2 framework lists PP2 as applicable at Supporting strength and uses the rule for genes with a low rate of benign missense variation in which missense variants are a common disease mechanism.
• This assessment uses the governing PTEN-specific framework rather than a variant-level classification from another source.

Sources

Reasoning

PTEN c.155A>T (p.Asp52Val) is a missense variant with REVEL score 0.95, exceeding the PTEN Expert Panel PP3 threshold of >0.7.

Rule

PTEN EP PP3 (Supporting): missense variant with REVEL score >0.7.

Evidence considered

• ClinGen PTEN Expert Panel Specifications v3.2 direct PP3 instruction for missense variants: REVEL score >0.7 supports PP3 at supporting strength.
• The variant-specific REVEL score is 0.95.

Sources

Reasoning

The PTEN Expert Panel specification permits BS3_Supporting when phosphatase activity is >0 per Mighell et al. 2018. The exact variant p.Asp52Val (D52V; NM_000314.8:c.155A>T) has a measured positive Cum_score of 0.113827986 and High_conf=True with passage of the standard-error filter, supporting retained/non-damaging phosphatase function at the VCEP-specified supporting strength.

Rule

PTEN VCEP v3.2: BS3_Supporting for an in vitro or in vivo functional study showing no damaging effect, specifically phosphatase activity >0 per Mighell et al. 2018, PMID: 29706350.

Evidence considered

• The PTEN VCEP Version 3.2 specification states that BS3_Supporting applies for phosphatase activity >0 per Mighell et al. 2018 (PMID:29706350).
• The VCEP Table S2 exact-match row for D52V/Asp52Val reports Cum_score 0.113827986, which is >0, with High_conf=True and High_conf_nature='Pass SE Filter'.
• The available VCEP assay result is high-confidence by the reported standard-error/concordance filtering flag; no additional orthogonal assay is required by the cited PTEN-specific BS3_Supporting rule.

Sources

Reasoning

NM_000314.8:c.155A>T is a missense substitution, p.(Asp52Val), not a null variant. It is neither a nonsense nor frameshift variant and does not alter a canonical splice dinucleotide; therefore it does not enter the PTEN-specific PVS1 decision tree for null variants and does not support PVS1.

Rule

PTEN Expert Panel PVS1 decision tree: apply only to qualifying null variants; this missense substitution is outside its eligible variant classes.

Evidence considered

• The selected PTEN transcript is NM_000314.8, and normalized annotation identifies c.155A>T as NP_000305.3:p.(Asp52Val), a missense change in exon 2.
• The PTEN Expert Panel PVS1 decision tree applies to null variant classes (nonsense, frameshift, canonical GT-AG splice-site disruption, and relevant exon deletions) and uses NMD/position only after a variant enters those classes.
• The variant-level PVS1 assessment identifies the consequence as missense, with no canonical splice-consensus involvement; NMD and truncation-position branches are consequently not applicable.

Sources

Reasoning

The PTEN Expert Panel missense functional specification uses Mighell et al. 2018 cumulative phosphatase/fitness score <= -1.11 for PS3_Moderate. The exact variant p.Asp52Val (D52V; NM_000314.8:c.155A>T) has a measured Cum_score of 0.113827986, High_conf=True, and passes the standard-error filter, so it does not demonstrate the damaging functional effect required for PS3.

Rule

PTEN VCEP v3.2: PS3_Moderate for phosphatase activity <= -1.11 per Mighell et al. 2018, PMID: 29706350; PS3_Supporting for phosphatase activity <50% of wild type or an abnormal assay not meeting PS3_Moderate.

Evidence considered

• The PTEN VCEP Version 3.2 specification states that PS3_Moderate applies when phosphatase activity is <= -1.11 per Mighell et al. 2018 (PMID:29706350).
• The VCEP Table S2 exact-match row for D52V/Asp52Val reports Cum_score 0.113827986, High_conf=True, and High_conf_nature='Pass SE Filter'.
• Because the measured score is positive and well above the damaging threshold, this assay result does not support PS3 at any specified strength.

Sources

Reasoning

Asp52 is outside the PTEN Expert Panel-defined catalytic motifs at residues 90-94, 123-130, and 166-168, and the case evidence reports no statistically significant PTEN D52 hotspot. Therefore the available evidence does not meet the PTEN-specific PM1 definition of a mutational hotspot or critical, well-established functional domain.

Rule

Located in a mutational hotspot and/or critical and well-established functional domain; PTEN VCEP-defined catalytic motifs are residues 90-94, 123-130, and 166-168.

Evidence considered

• The PTEN VCEP Version 3.2 PM1 rule defines the included catalytic motifs as NP_000305.3 residues 90-94, 123-130, and 166-168.
• The variant affects NP_000305.3 residue 52, not one of those defined motifs.
• The hotspot search for PTEN D52 returned no statistically significant hotspot.

Sources

Reasoning

The variant produces a single amino-acid substitution, p.(Asp52Val), without an in-frame insertion/deletion, stop-loss, or protein extension. It therefore causes no protein length change and does not meet the PTEN-specific PM4 rule.

Rule

PTEN Expert Panel PM4: in-frame insertion/deletion affecting at least one PM1 catalytic-motif residue, or a protein-extension variant.

Evidence considered

• Normalized transcript/protein annotation shows a missense substitution, NM_000314.8:c.155A>T / NP_000305.3:p.(Asp52Val), with no change in protein length.
• The PTEN Expert Panel specifies PM4 for protein length changes from in-frame insertions/deletions that affect at least one catalytic-motif residue, or for variants causing protein extension; neither variant class is present.

Sources

Reasoning

BA1 is not met. The PTEN-specific VCEP threshold is filtering allele frequency >0.00056 (>0.056%) in gnomAD; NM_000314.8:c.155A>T (p.Asp52Val) is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, so the threshold is not exceeded.

Rule

PTEN VCEP BA1: apply at filtering allele frequency >0.00056 (>0.056%) in gnomAD.

Evidence considered

• ClinGen PTEN Expert Panel Specification v3.2 defines BA1 as gnomAD filtering allele frequency >0.00056 (>0.056%).
• The case bundle reports the variant as absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0; therefore no population allele frequency supports BA1.

Sources

Reasoning

BS1 is not met. The PTEN-specific VCEP defines BS1 Strong for gnomAD filtering allele frequency 0.000043 to 0.00056 (0.0043% to 0.056%) and BS1 Supporting for 0.0000043 to 0.000043 (0.00043% to 0.0043%). The variant is absent from the evaluated gnomAD datasets, with no allele frequency in either range.

Rule

PTEN VCEP BS1: Strong at gnomAD filtering allele frequency 0.000043 up to 0.00056; Supporting at 0.0000043 up to 0.000043.

Evidence considered

• ClinGen PTEN Expert Panel Specification v3.2 defines BS1 Strong as filtering allele frequency 0.000043 up to 0.00056 and BS1 Supporting as 0.0000043 up to 0.000043 in gnomAD.
• The case bundle reports absence of the variant from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0; no frequency, ancestry-specific frequency, or threshold artifact was identified.

Sources

Reasoning

The PTEN Expert Panel permits BP4 for missense variants only when REVEL is <0.5. This missense variant has REVEL 0.95, so BP4 is not met. SpliceAI max delta 0.11 is not used to apply BP4 here because the PTEN BP4 splicing path is specified for synonymous or intronic variants and requires concordant SpliceAI and VarSeak results.

Rule

PTEN EP BP4 (Supporting): missense REVEL <0.5; separate splicing path applies to synonymous or intronic variants with concordant SpliceAI and VarSeak predictions.

Evidence considered

• ClinGen PTEN Expert Panel Specifications v3.2 direct BP4 instruction for missense variants: REVEL score <0.5; for synonymous or intronic variants, use concordant benign SpliceAI and VarSeak predictions.
• The variant-specific REVEL score is 0.95, which does not meet the PTEN BP4 missense threshold.
• SpliceAI reports a maximum delta score of 0.11, but no VarSeak result is available and this is a missense, not synonymous or intronic, variant.

Sources

Reasoning

The variant is NP_000305.3:p.(Asp52Val), but the case bundle contains no established pathogenic or likely pathogenic alternate nucleotide change producing the same amino-acid substitution. ClinVar has no record for this variant and the literature pass identified no PMIDs; these findings do not establish that no qualifying same-amino-acid comparator exists.

Rule

Same amino acid change as a previously established pathogenic variant regardless of nucleotide change; PTEN VCEP strength: Strong.

Evidence considered

• The normalized variant is NM_000314.8:c.155A>T, NP_000305.3:p.(Asp52Val) (p.D52V).
• The PTEN Expert Panel Version 3.2 rule requires the same amino-acid change as a previously established pathogenic variant for PS1 at strong strength.
• ClinVar returned no result for this variant, and the literature pass reported zero PMIDs; neither result proves absence of a qualifying comparator.

Still missing

• No independently verified pathogenic same-amino-acid comparator was identified in the available case evidence.
• A comprehensive review of external PTEN variant databases and literature for alternate nucleotide changes yielding p.Asp52Val is still required.

Sources

Reasoning

No case-level proband de novo observation or parental testing result is documented in the consolidated evidence bundle. Therefore PS2 cannot be assessed. The PTEN Expert Panel specification requires a de novo observation in a patient with disease and no family history; strong evidence requires both maternity and paternity confirmation, and very strong evidence requires the specified combination of proven or assumed observations.

Rule

De novo (both maternity and paternity confirmed) observation in a patient with the disease and no family history; two proven OR four assumed OR one proven + two assumed de novo observations support Very Strong.

Evidence considered

• The case bundle identifies the applicable framework as the ClinGen PTEN Expert Panel Specifications, Version 3.2.
• The bundle contains no case-level parental testing, de novo, proband, or family-history evidence for NM_000314.8:c.155A>T (p.Asp52Val).
• PTEN VCEP PS2 rule: de novo with both maternity and paternity confirmed in a patient with disease and no family history supports PS2 Strong; two proven, four assumed, or one proven plus two assumed observations support PS2 Very Strong.

Still missing

• Proband-level disease phenotype and family-history documentation
• Variant testing results in both biological parents
• Confirmation of maternity and paternity
• Number of independent de novo observations, if any

Sources

Reasoning

No affected-case series, phenotype specificity scores, or case-control enrichment data for PTEN c.155A>T (p.Asp52Val) are present in the case evidence bundle. The PTEN Expert Panel framework requires a cumulative phenotype-specificity score or a sufficiently powered case-control result for PS4.

Rule

PTEN Expert Panel PS4: phenotype-specificity score or sufficiently powered case-control enrichment; PS4 may not be applied if BS1 applies.

Evidence considered

• The PTEN Expert Panel specifies PS4 by cumulative phenotype-specificity scores: supporting for 1-1.5, moderate for 2-3.5, strong for 4-15.5, and very strong for at least 16. It also permits a sufficiently powered case-control study with odds ratio greater than 2, p<0.05, and 95% confidence-interval lower bound greater than 1.5 for a PHTS component phenotype.

Still missing

• Independent affected probands with documented adult Cleveland Clinic or pediatric phenotype scores, or a sufficiently powered case-control study for this exact variant, are needed.

Sources

Reasoning

The PTEN VCEP PM5 rule requires a different missense change at the same amino-acid residue that is pathogenic or likely pathogenic, with the queried change having a BLOSUM62 score equal to or less than the known comparator. The collected PM5 candidate summary reports five candidates reviewed but zero same-residue candidates, and no literature PMIDs were available; this is insufficient to conclude that no qualifying comparator exists.

Rule

Missense change at an amino-acid residue where a different missense change determined to be pathogenic or likely pathogenic has been seen before, and the queried variant has a BLOSUM62 score equal to or less than the known variant; PTEN VCEP strength: Moderate.

Evidence considered

• The PM5 candidate summary reports total_candidates_seen=5 and same_residue_candidates=0, with a recommendation of no useful candidates found.
• The PTEN VCEP Version 3.2 PM5 rule requires a different pathogenic or likely pathogenic missense change at the same amino-acid residue and a queried-variant BLOSUM62 score equal to or less than the known variant.
• The literature pass found no PMIDs for this case.

Still missing

• No qualifying pathogenic or likely pathogenic alternate missense change at Asp52 was identified in the collected candidates.
• BLOSUM62 comparison cannot be performed without a validated same-residue pathogenic or likely pathogenic comparator.

Sources

Reasoning

No presumed or assumed de novo occurrence is documented for this variant in the case bundle, and no proband phenotype or family-history information is available to apply the PTEN-specific PM6 rules.

Rule

Assumed de novo without confirmation of paternity and maternity in a proband with disease and no family history supports Moderate; two presumed de novo probands or one with a highly specific phenotype supports Strong; two proven, four assumed, or one proven plus two assumed observations support Very Strong.

Evidence considered

• The case bundle identifies the applicable framework as the ClinGen PTEN Expert Panel Specifications, Version 3.2.
• The bundle contains no case-level PM6 observations, parental results, proband phenotype, or family-history data for NM_000314.8:c.155A>T (p.Asp52Val).
• PTEN VCEP PM6 rule: an assumed de novo observation without confirmed maternity and paternity in a proband with disease and no family history supports PM6 Moderate; two presumed de novo probands or one presumed de novo observation in a highly specific phenotype support PM6 Strong; the specified combinations support PM6 Very Strong.

Still missing

• Documented proband with PTEN hamartoma tumor syndrome or qualifying disease phenotype
• Evidence that the variant is absent from both tested parents or otherwise presumed de novo
• Maternity and paternity confirmation status
• Number of independent presumed de novo observations
• Assessment of whether any proband has a highly specific phenotype qualifying for the PTEN PS4 pathway

Sources

Reasoning

No familial segregation data, affected relatives, informative transmissions, or meiosis count is documented in the consolidated evidence bundle. PP1 therefore cannot be assessed.

Rule

Co-segregation with disease in multiple affected family members: 3 or 4 meioses Supporting, 5 or 6 Moderate, and at least 7 meioses across at least two families Strong.

Evidence considered

• The case bundle identifies the applicable framework as the ClinGen PTEN Expert Panel Specifications, Version 3.2.
• The bundle contains no segregation, pedigree, affected-relative, genotype-transmission, or meiosis evidence for NM_000314.8:c.155A>T (p.Asp52Val).
• PTEN VCEP PP1 rule: 3 or 4 meioses are required for Supporting, 5 or 6 meioses for Moderate, and at least 7 meioses across at least two families for Strong, with co-segregation in multiple affected family members.

Still missing

• Pedigree or family structure
• Affected relatives with phenotype consistent with PTEN hamartoma tumor syndrome
• Genotype results for informative relatives
• Count of informative meioses and family count

Sources

Reasoning

No exact-variant ClinVar record is present for PTEN c.155A>T (p.Asp52Val); consequently, there is no exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic assertion to support PP5.

Rule

PP5 is considered only for an exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic assertion.

Evidence considered

• ClinVar search for PTEN c.155A>T returned no result; the case evidence states that this variant is absent from ClinVar.

Still missing

• An exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic assertion would be required.

Sources

Reasoning

BS2 cannot be assessed from the available evidence. The PTEN VCEP requires the variant to be observed in the homozygous state in a healthy or PHTS-unaffected individual; one observation is sufficient when homozygosity is confirmed by parental testing, otherwise two independent homozygous observations are required. The population records in this case report the variant as absent and provide no homozygote observations or clinical/parental data.

Rule

PTEN VCEP BS2: observed homozygous in a healthy or PHTS-unaffected individual; one observation if confirmed, two if not confirmed; Supporting if BS1 is also applied.

Evidence considered

• ClinGen PTEN Expert Panel Specification v3.2 requires a confirmed homozygous observation in a healthy or PHTS-unaffected individual for BS2 Strong; two homozygous observations are required when homozygous status is not confirmed, and BS2 is downgraded to Supporting if BS1 is also applied.
• The case bundle reports the variant as absent from the evaluated population datasets and contains no homozygote count, individual-level health status, or parental confirmation.

Still missing

• No confirmed homozygous observation in a healthy or PHTS-unaffected individual.
• No parental testing or other phase information.
• No independent homozygous observations without confirmed phase.

Sources

Reasoning

No affected family members, familial genotype-phenotype comparisons, or non-segregation observations are documented. Lack of segregation cannot be inferred from the absence of family data, so BS4 cannot be assessed.

Rule

Lack of segregation in affected members of one family supports Supporting; lack of segregation in affected members of two or more families supports Strong.

Evidence considered

• The case bundle identifies the applicable framework as the ClinGen PTEN Expert Panel Specifications, Version 3.2.
• The bundle contains no case-level evidence of affected relatives who lack the variant and no documented lack of segregation for NM_000314.8:c.155A>T (p.Asp52Val).
• PTEN VCEP BS4 rule: lack of segregation in affected members of one family supports BS4 Supporting; lack of segregation in affected members of two or more families supports BS4 Strong.

Still missing

• Family pedigree and list of affected relatives
• Genotype results for affected relatives
• Phenotype ascertainment and consistency in affected relatives
• Determination of whether non-segregation occurs in one or more families

Sources

Reasoning

BP2 is not assessed. The PTEN-specific framework permits BP2 at Supporting strength only for this variant observed in trans with a pathogenic or likely pathogenic PTEN variant, or for at least three observations in cis and/or phase unknown with different pathogenic or likely pathogenic PTEN variants. The case-evidence bundle contains no documented co-occurring pathogenic/likely pathogenic PTEN variant, affected-proband observation, or phase information meeting either condition.

Rule

ClinGen PTEN Expert Panel Specifications Version 3.2 BP2: Supporting if observed in trans with a pathogenic or likely pathogenic PTEN variant, or if there are at least three observations in cis and/or phase unknown with different pathogenic/likely pathogenic PTEN variants.

Evidence considered

• The PTEN-specific BP2 rule requires either observation in trans with a pathogenic or likely pathogenic PTEN variant, or at least three observations in cis and/or phase unknown with different pathogenic/likely pathogenic PTEN variants.
• The consolidated case-evidence bundle reports no variant-specific literature PMIDs and contains no documented phase, cis/trans, co-occurrence, or affected-proband observation for NM_000314.8:c.155A>T (p.Asp52Val).

Still missing

• Documented co-occurrence of NM_000314.8:c.155A>T (p.Asp52Val) with a pathogenic or likely pathogenic PTEN variant.
• Experimental or family-based phase determination showing trans, or at least three qualifying cis and/or phase-unknown observations with different pathogenic/likely pathogenic PTEN variants.
• Affected-proband and inheritance information for any qualifying co-occurrence observation.

Sources

Reasoning

No cases with an alternate molecular diagnosis are provided. The PTEN Expert Panel requires at least two such cases, a highly penetrant alternate gene/disorder, and personal/family history demonstrating no overlap with PTEN.

Rule

PTEN Expert Panel BP5: at least two cases with a highly penetrant alternate molecular diagnosis and non-overlapping PTEN history.

Evidence considered

• The PTEN Expert Panel specifies that BP5 requires at least two cases; the alternate gene/disorder must be highly penetrant and the patient's personal/family history must demonstrate no overlap between the alternate condition and PTEN.

Still missing

• At least two independently documented cases with a highly penetrant alternate molecular diagnosis and non-overlapping PTEN personal/family history are needed.

Sources

Reasoning

No exact-variant ClinVar record is present for PTEN c.155A>T (p.Asp52Val); consequently, there is no exact-variant ClinVar expert-panel Benign or Likely benign assertion to support BP6.

Rule

BP6 is considered only for an exact-variant ClinVar expert-panel Benign or Likely benign assertion.

Evidence considered

• ClinVar search for PTEN c.155A>T returned no result; the case evidence states that this variant is absent from ClinVar.

Still missing

• An exact-variant ClinVar expert-panel Benign or Likely benign assertion would be required.

Sources